The long-range goals of the PI are to evaluate the mechanisms that regulate blood flow delivery in heart failure (HF), an important disease of the aged. The short-range goals are to determine: 1) the interstitial metabolites that may evoke the muscle metaboreflex in HF, 2) the effects of the reflex on blood flow to exercising muscle, and 3) the effects of exercise conditioning on reflex responses to exercise in HF. Our recent work has suggested that the muscle metaboreflex is engaged at low levels of rhythmic exercise in HF patients. This premature reflex engagement was associated with increased peroneal nerve muscle sympathetic nerve activity. To date no one has characterized the interstitial concentrations of the muscle metabolites that may evoke this reflex in normal young subjects, aged subjects and those with HF. We have begun using the microdialysis method to directly determine interstitial concentrations of potential metaboreceptor stimulants in humans. We can now measure interstitial lactate, phosphate, adenosine, K+ and H+ in resting and exercising skeletal muscle. In this proposal we will utilize this method during rhythmic quadriceps contractions in subjects with HF and old and young controls as we simultaneously measure opposite leg muscle sympathetic nerve activity (MSNA). We hypothesize that K+ and phosphate will correlate best with MSNA. We will then examine the effects of quadriceps muscle conditioning on muscle metaboreflex activity in the three subject groups discussed above. We speculate that conditioning will increase limb blood flow, reduce metabolite production and in the process reduce MSNA responses to quadriceps contractions more in HF subjects than in controls. In separate experiments, we will employ a bretylium Bier block of the right upper extremity to reduce sympathetic vasoconstrictor tone and determine the effects this intervention has on limb blood flow and MSNA. Novel components of the work described include the use of multiple state of the art human investigative techniques including microdialysis, peroneal nerve recordings of sympathetic traffic, Doppler flow measurements, and 31P NMR spectroscopy. This K24 award will reduce the PI's administrative and clinical commitment and thereby allow him to continue his human investigative work and to spend more time training talented patient-oriented investigators.